The median time on the ALK inhibitor increased from 10.1 months without ablative therapy to 21.1 months with aggressive treatment of isolated lesions.

All patients who had lesion ablation by radiation or surgery had disease control at 6 months, and disease remained in check in about 80% at 12 months, according to a small clinical study reported at the American Society for Radiation Oncology.

"LAT [local ablative therapy] has demonstrated an excellent 6- and 12-month lesion control rate and is well tolerated," said Gregory Gan, MD, of the University of Colorado in Aurora. "LAT has provided an additional 11 months of systemic disease control and allowed for extending use of crizotinib. Extending exposure to crizotinib was associated with longer overall survival."

Crizotinib has become standard systemic therapy for the subset of patients with ALK-positive NSCLC. However, reported progression-free survival (PFS) has ranged between 8 and 10 months, reflecting emergence of drug-resistant clonagens.

In some patients, the resistant lesions are isolated or limited to a single region. The traditional therapeutic paradigm has been to switch therapy at progression, regardless of how limited the progression might be.

"We asked whether there is an alternative to this treatment paradigm," said Gan. "We have extensive experience using local ablative therapy to treat patients with limited sites of progression while on targeted systemic agents."

The term oligoprogression has been coined to describe limited progression during systemic therapy. More specifically for patients treated with crizotinib, Gan and colleagues define oligoprogression as good disease control overall, limited toxicity, and emergence of four or fewer discrete sites of active extra-CNS disease.

By ablating the isolated lesions, clinicians have hoped to extend the time on crizotinib, along with the good overall disease control, resulting in better overall survival.

The investigators reviewed records of patients who had participated in clinical trials of crizotinib for metastatic ALK-positive NSCLC and met criteria for oligoprogressive disease. They identified 38 patients, 12 of whom had local ablation of a total of 26 drug-resistant lesions by hypofractionated radiotherapy (16 to 54 Gy) or by surgery (one lesion). Gan emphasized the need to be maximally aggressive in the approach to local ablation.

In the patients who underwent ablation, crizotinib therapy continued until development of unacceptable toxicity or progression beyond the state of oligoprogressive disease. Crizotinib was withheld only on the day of ablative therapy.

All 12 patients had local disease control at 6 months, and 10 of 12 maintained local control at 12 months. The median biological equivalent dose (BED) of radiation therapy was 58.6 Gy. Analysis of disease control for individual lesions showed that a BED >100 Gy was associated with better disease control. Evaluation of other dose metrics showed a similar association between higher dose and better disease control.

"The take-home point is that you want to try to be maximally aggressive with each lesion, but taking into consideration the normal tissue parenchyma and respecting the normal radiologic tissue tolerance constraints," said Gan.

The median time to first progression was 10.1 months in the patients who underwent local ablative therapy. Normally, patients would stop taking crizotinib at that point. Following local ablation, the median time to subsequent progression was 11 months, resulting in a 21.1-month median exposure time to crizotinib.

Comparing survival and crizotinib exposure, the investigators found that patients had better overall survival at 2 years if they remained on crizotinib for at least 12 months.

Given the study's limitations and lack of clear explanation for the outcomes, Gan cautioned against making too much of the findings at this point.

"As enticing as our results may be, we do recommend that a prospective clinical trial be performed to try to validate our results," he said.

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